Growth hormone acts through binding to membrane receptors that belong to the cytokine receptor superfamily (Finidori, Vitam. Horm. 59: 71-97 (2000)). Ligand binding induces receptor dimerization and activation of the receptor-associated kinase JAK-2, resulting in phosphorylation of the kinase, the receptor and many cellular proteins (Finidori (2000), supra). Activation by growth hormone is very transient and several mechanisms are involved in downregulation, including internalization and degradation of the receptor and recruitment of phosphatases or specific inhibitors of the JAK/Stat pathway, namely the SOCS proteins (Finidori (2000), supra).
There are variant forms of human growth hormone (hGH) which include a disulfide dimer, a glycosylated form (20 kD hGH) and two pituitary peptides made up of portions of 22 kD hGH (Lewis et al., Endocr. J. 47 Suppl: S1-8 (March 2000)). The two pituitary peptides (hGH (1-43) and hGH (44-191)) have, respectively, insulin-potentiating and anti-insulin properties (Lewis et al. (March 2000), supra). The smaller peptide may be useful in decreasing the amount of exogenous insulin required by diabetics, whereas the larger peptide may be involved in diabetic retinopathy (Lewis et al. (March 2000), supra).
The increased availability of growth hormone (GH) in the mid-1980s, due to advances in recombinant DNA technology, has allowed research into the use of this hormone at physiological dosage as replacement therapy for adults and children with GH deficiency (GHD) (see, e.g., Carroll et al., Trends Endocrinol. Metab. 11(6): 231-238 (August 2000)) and at pharmacological dosages as a possible therapeutic agent for a number of disease states (Murray et al., Expert Opin. Pharmacother. 1(5): 975-990 (July 2000); see, also, Wit, Endocr. Regul. 34(1): 28-32 (March 2000)). Such disease states include frailty associated with ageing, osteoporosis, morbid obesity, cardiac failure, major thermal injury, hypoglycemic unawareness in diabetes mellitus (Sonksen et al., U.S. Pat. No. 5,426,096, issued Jun. 20, 1995), various acute and chronic catabolic conditions (Murray et al. (July 2000), supra; see, also, Mehls et al., Growth Horm. IGF Res. 10 Suppl. B: S31-37 (April 2000)) and intoxication with poisonous substances that are degraded in the liver by microsomal enzymes (Jorgensen, U.S. Pat. No. 4,816,439, issued Mar. 28, 1989). In combination with DHEA, its use has been proposed for regenerating an involuted thymus (Fahy, International Patent Application WO 95/32991, published Dec. 7, 1995).
GHD in humans is currently treated by growth hormone injection. The problem with such a treatment method is that injections are required every day or couple of days (MacGillivray et al., J. Clin. Endocrinol. Metab. 81(5):1806-1809 (May 1996)). The present invention seeks to overcome such a problem. This and other objects and advantages, as well as additional inventive features, will become apparent from the detailed description provided herein.